Pediatrics and Neonatology (2016) 57, 89e96

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REVIEW ARTICLE

Childhood Atopic Dermatitis in Taiwan

I-Jen Wang a,b,c,*, Jiu-Yao Wang d, Kuo-Wei Yeh e

a
Department of Pediatrics, Taipei Hospital, Ministry of Health and Welfare, Taipei, Taiwan
b
Institute of Environmental and Occupational Health Sciences, College of Medicine, National
Yang-Ming University, Taipei, Taiwan
c
Department of Health Risk Management, China Medical University, Taichung, Taiwan
d
Department of Pediatrics, College of Medicine, National Cheng Kung University, Tainan, Taiwan
e
Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial
Hospital at Linkuo, and Chang Gung University College of Medicine, Taoyuan, Taiwan

Received Mar 31, 2015; received in revised form Aug 3, 2015; accepted Aug 24, 2015
Available online 25 September 2015

Key Words The prevalence of atopic dermatitis (AD) appears to have increased dramatically over the past
atopic dermatitis; decades. It is generally believed that such rapid increase in prevalence cannot be explained
environmental fully by genetic factors. Environmental factors might play a role in such an increment. Children
factors; with AD are most likely to suffer considerable school absences, family stress, and health care
prevention expenditures. Because the onset of AD occurs relatively early in life, identification of early life
risk factors and early management for AD to prevent the development of atopic march are of
critical importance. However, there is still no consensus on coordinated prevention and man-
agement for AD in Taiwan. In this review, we discuss the specific risk factors of AD and impor-
tant results of recent articles on AD from Taiwan. The management and prevention strategies
of AD for Asian skin are also discussed.
Copyright 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction have increased dramatically over the past decades.1 Ac-

Atopic dermatitis (AD) is a chronic inflammatory pruritic skin
disease that affects a large number of children in industri-
alized countries. In Taiwan, the prevalence of AD appears to
* Corresponding author. Department of Pediatrics, Taipei Hospital,
Ministry of Health and Welfare, Number 127, Su-Yuan Road,
Hsin-Chuang District, New Taipei City 242, Taiwan.
E-mail address: wij636@gmail.com (I.-J. Wang).
cording to Taiwan national birth cohort, AD was noted in 118
of 1760 (6.7%) infants at 6 months of age in 2005 and in 1584
(7.9%) out of 19,968 children at 18 months in 2007.2,3 In 6-
to7-year-old schoolchildren in Taipei, the prevalence of AD
significantly increased in 2007 (29.8%) compared to 1994
(23.9%) and 2002 (26.3%).4 Because population genetic vari-
ability does not change with such rapidity, changing envi-
ronmental factors are likely to be responsible for the rise in
the number of AD. The quality of life of children with AD and
their families is obviously affected.5 It leads to considerable

http://dx.doi.org/10.1016/j.pedneo.2015.08.005
1875-9572/Copyright 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
90
financial and psychosocial burden to individuals and society.
The rising prevalence in the pattern of skin diseases and
psychosocial burden makes AD one of the most important
groups of chronic childhood diseases.
Because the onset of AD occurs relatively early in life,
identification of early life risk factors among genetically
susceptible children and early management for AD to pre-
vent the development of atopic march are of critical
importance. However, we still lack a consensus on pre-
vention and management of AD in Taiwan. In this review,
we discuss the specific risk factors and important results
from recent primary literature articles in Taiwan. Then, we
discuss how to take care of the AD skin in our humid climate
and how to manage children who do not respond to con-
ventional treatment.
2. Risk factors
The development and phenotypic expression of AD depends
on a complex interaction among genetic factors, perinatal
environmental exposure to allergens, and nonspecific
adjuvant factors, such as pollution, infections, and cli-
mates.1,6 Food allergens may be the major trigger of AD in
early life, after which the role of environmental aero-
allergens becomes more important and may be associated
with respiratory sensitization.6
2.1. Hereditary factors
AD may be inherited preferentially through the maternal
line.2 It was reported that maternal history of AD, maternal
grandparents history of AD, higher family income, and higher
maternal education level increased the risk of pediatric AD.2
The mode of inheritance and genes involved are not clear.
Genes associated with adaptive immunity and skin-barrier
formation have been involved in the development of AD.
For example, single nucleotide polymorphisms in Toll-like
receptors, ST2, interleukin (IL)-3, IL-4, IL-5, IL12RB1, and
IL-13 have been shown to be associated with the pathogenesis
of AD.7 Genetic mutations in filaggrin (FLG), which is essen-
tial for the maintenance of the skin-barrier function, are
significantly associated with the risk of AD and disease
severity in different ethnic populations.8 Among Chinese in-
dividuals, the FLG P478S polymorphism may confer suscep-
tibility to the development of AD and may be modified by
immunoglobulin E (IgE) levels.9 Another recent study indi-
cated that genetic polymorphisms of ORAI1 are involved in
the susceptibility to AD in Japanese and Taiwanese pop-
ulations.10 Genome-wide association study also identified
two new susceptibility loci at 5q22.1 and 20q13.33 for AD in
the Chinese Han population.11 Determining the candidate
susceptibility genes for AD will not only help us understand
the pathophysiology but will also affect the response to
therapy, which is important in pharmacogenetics.
2.2. Allergens
Allergens play an essential role in AD, either intrinsic or
extrinsic.12 They provoke cutaneous inflammation via IgE-
dependent and cell-mediated immune reactions.12 Sensiti-
zation to food allergens (egg, milk, wheat, soy, and peanut) is
I.-J. Wang et al
associated with AD and related to disease severity and
persistence.13 Only in a minority of those with food sensiti-
zation (about 33% with moderate to severe AD) are food al-
lergens of clinical relevance, as demonstrated by food
challenge tests.13 It is well established that food can exac-
erbate AD both through allergic and nonallergic hypersensi-
tivity reactions. Furthermore, direct food contact with the
skin might be an important factor for the aggravation of AD.14
Beyond the age of 5 years, food allergy is frequently
outgrown, but sensitization to inhalant allergens is common.6
Exposure to aeroallergens (mites, animal danders, cockroach,
molds, and pollen) has been clearly shown to increase the risk
factors for AD and AD severity.1 In humid climate such as that
found in Taiwan, fungi are especially important and their
impacts might start at the early infant stage.15 Skin lesions
can develop after inhalation challenge with aeroallergens in
patients with AD. Moreover, epicutaneous application of
aeroallergens on uninvolved skin of patients with AD elicits
eczematoid reactions in patients with AD.14 Therefore,
identification of individualized allergen sensitization by skin
prick tests or allergen-specific IgE may provide a strategy for
better control of AD and avoidance of atopic march.12
2.3. Infection
The hygiene hypothesis offers an explanation of why
certain environmental exposures early in life may suppress
or activate clinical disease. There is evidence to support an
inverse relationship between AD and endotoxin, early day
care, and farm animal and dog exposure in early life.16
Helminth infection at least partially protects against AD.
This is not the case for viral and bacterial infections.16 The
effect of routine childhood vaccinations on AD risk is
controversial. There is a potential risk for AD after
receiving Hib combination vaccines. However, the vacci-
nation is important to public health, and therefore the
observation requires further investigations.3
2.4. Pollutants and chemicals
During the same period that modern pollutants and chem-
icals have increased, there has been a remarkable increase
of allergy in children. Smoke exposure during pregnancy has
been demonstrated to increase the risk of AD in children.17
Exposure to environmental tobacco smoke in childhood is
associated with the development of adult-onset AD.18
Moreover, air pollutants, such as hydrogen sulfide, nitro-
gen dioxide, carbon monoxide, and formaldehyde, may
increase the prevalence and severity of AD.1,19 Exposures to
perfluorinated chemicals, a kind of endocrine-disrupting
chemicals, were reported to be positively correlated with
blood IgE levels and AD.20 Early phthalate exposure may
also increase the risk of allergic sensitization and AD.21 The
biological effects of these pollutants are different
depending on the presence or absence of an antigen, which
is called an adjuvant effect.22
2.5. Gene and environment interaction
AD is a complex genetic disorder influenced by environ-
mental factors. Based on hereditary and environmental
Atopic Dermatitis in Taiwan
factors, boys, maternal education levels >12 years, both
parents with AD, renovation and painting of the house
during pregnancy, and fungus on walls at home have the
highest predicted probability of AD.23 Genetic poly-
morphisms in GSTM1 and GSTP1 were reported to be
responsible for the susceptibility to AD with regard to
smoke exposure.24 Moreover, the effect of smoke exposure
on the risk for AD may be mediated through DNA methyl-
ation.25 We also found that FLG genetic polymorphisms may
be modified by allergen exposure to confer susceptibility to
the development of AD.9 Future studies to assess the effect
of epigenetic changes after environment exposures on the
risk of AD are warranted.
3. Mechanisms
3.1. Immunologic pathways
AD inflammation is associated with increased Th2 cells in
acute skin lesions, but chronic AD results in the infiltration
of inflammatory dendritic cells, macrophages, and eosino-
phils. IL-12 production by these various cell types results in
the switch to a Th1-type cytokine milieu associated with
increased interferon-g expression.26 Skin injury by envi-
ronmental allergens, scratching, or microbial toxins acti-
vate keratinocytes to release proinflammatory cytokines
that induce the expression of adhesion molecules on
vascular endothelium and facilitate the extravasation of
inflammatory cells into the skin. Keratinocyte-derived
thymic stromal lymphopoietin may enhance Th2 cell dif-
ferentiation. Keratinocyte apoptosis, which was induced by
soluble Fas ligand, may break down epithelial integrity and
initiate the development of AD.27
3.2. Skin barrier dysfunction
Skin barrier dysfunction has emerged as a critical driving
force in the initiation and exacerbation of AD and the
atopic march in allergic diseases.28 The genetically
determined barrier deficiency and barrier disruption by
environmental proteases in skin are considered to enhance
penetration of allergens, increase the risk of sensitization
to allergens, and contribute to the exacerbation of allergic
diseases. It is proposed that the paradigm of AD primarily
due to immunologic aberration inside-out should be
shifted to include a primary defect in barrier function
outside-in.29 Cross-talk between skin barrier abnormal-
ities and aberrant immune responses is evidenced by
epidermal abnormalities enhancing the release of
keratinocyte-derived cytokines and chemokines, resulting
in modulation of skin immune responses.18
4. Treatment
The management of AD should better follow the stepwise
treatment to reduce the use of systematic steroid (Figure 1).
The need for more effective AD therapies with fewer side
effects has pushed researchers to develop new therapies
and to recycle traditional treatments for use in a novel way.
First-line therapy includes topical corticosteroids and
91
emollient use, followed by topical calcineurin inhibitors,
phototherapy, and systemic therapy in difficult cases.
Innovative therapies include proactive treatment, barrier
therapy, novel antistaphylococcal treatments, new immune
modulatory agents, exclusionary diets, and probiotics.
4.1. Topical treatment
4.1.1. Topical corticosteroids
This is the most common and effective treatment. Corti-
costeroids are grouped into different classes (mild, mod-
erate, strong, and very strong preparations). For younger
children, lowest potency corticosteroids are recom-
mended. When all lesions have mostly cleared by an
intensive topical corticosteroid, proactive treatment with
long-term and low-dose intermittent application (2 to 3
weekly) to the former affected areas is suggested. This
strategy is different from reactive treatment in which the
treatment consists of daily application of topical cortico-
steroid on as-needed basis.30 The proactive treatment is
being increasingly promoted because the overall quantity
of corticosteroid used is smaller than that used with the
reactive treatment. Moreover, the risk of an exacerbation
of the AD is minor.30 Glazenburg et al31 studied the
biweekly application of fluticasone propionate cream in a
16-week, placebo-controlled, randomized study of moder-
ately to severely affected children. The risk of an AD flare
in the reactive treatment group was more than twice as
high as in the proactive treatment group.31
4.1.2. Calcineurin inhibitors
Although the U.S. Food and Drug Administration (FDA) set a
boxed warning for topical calcineurin inhibitors, they are
still officially licensed topical medications for AD in other
guidelines (National Institute for Health and Care Excel-
lence 2007, American Academy of Dermatology (AAD) 2014,
and International consensus conference on atopic derma-
titis II (ICCAD II)). The U.S. FDA recommends caution when
prescribing or using Pimecrolimus cream (Novartis Pharma)
and Tacrolimus ointment (Astellas Pharma US Inc.) because
of a potential cancer risk. These medicines may only be
used as directed and only after trying other treatment
options.32 Calcineurin inhibitors are not approved for chil-
dren younger than 2 years of age.
4.1.3. Wet wrap therapy
After the medication or moisturizer has been applied onto
the affected area, it is wrapped with a few layers of wet
gauze, followed by layers of dry gauze and secured with
elastic stretch. Such therapy is very effective for severe AD
because it reduces pruritus and inflammation by preventing
scratching, enhancing moisturizing of the skin, and improving
the penetration of topical corticosteroids.33 Generally, wet
wrap therapy is applied for no more than 2 weeks, and sig-
nificant improvement can be seen after 3 days.
4.2. Systematic treatment
Systematic steroids are not recommended for children with
AD unless they are required to manage asthma exacerba-
tions; they are given as a short-term transition protocol to
92
Figure 1 Stepwise management of AD. AD Z atopic dermatitis; CyA Z Cyclosporine A; SCORAD Z scoring atopic dermatitis;
TCI Z topical calcineurin inhibitors; TCS Z topical corticosteroids.
nonsteroidal systemic immunomodulatory agents, or the
rash covers large areas of the body. Most providers use a
dosage range of 0.5e1.0 mg/kg/d.34 Flare of the AD upon
steroid discontinuation may be expected.
Antihistamines are often used to treat itching and to
help patients sleep when severe night itching is a problem.
However, histamines are not always involved in AD itching,
so these medicines may not help all patients with the
condition.
Antibiotic, antiviral, or antifungal medicines are used to
treat an infected rash. AD skin has been found to be defi-
cient in antimicrobial peptides needed for host defense
against pathogens.35 Patients with AD have an increased
propensity toward disseminated infections with Staphylo-
coccus aureus, herpes simplex or vaccinia virus because of
deficiency in antimicrobial peptides.36 Combination ther-
apy of anti-inflammatory drugs and antibiotics in AD pa-
tients with secondary bacterial infection, exacerbated AD,
or poorly controlled AD is suggested.35 However, a 2010
Cochrane review of randomized control trials did not find
any clear benefit for topical antibiotics/antiseptics, anti-
bacterial soaps, or antibacterial bath additives in AD.37
Although the addition of a topical antibiotic to a topical
steroid reduces the amount of S. aureus isolated from the
skin, the combination has not been found to improve either
global outcomes or disease severity compared with the
steroid alone. Thus, topical antimicrobial preparations are
not generally recommended in the treatment of AD. They
can be associated with contact dermatitis, and there is also
concern that their use could promote wider antimicrobial
drug resistance.37 The new AAD guidelines also state that
the use of systemic antibiotics in the treatment of nonin-
fected AD is not recommended. Systemic antibiotics are
recommended in patients with clinical evidence of bacte-
rial infections in addition to standard treatments for AD.38
Generally, a systematic first- or second-generation cepha-
losporin for 7e10 days is recommended.
UV light, UVA1 and narrowband-UVB, with or without
additional medicine, appeared to be effective treatment
modalities for the reduction of clinical signs and symptoms
of AD.39 It is interesting to ascertain whether combination
therapy using narrowband UVB and pimecrolimus has an
I.-J. Wang et al
additive or synergistic effect. However, a study in Taiwan,
supporting the consensus of the European Working Group on
Atopic Dermatitis, did not show any significant therapeutic
difference between monotherapy and combination ther-
apy.40,41 Combining phototherapy with pimecrolimus is
inadvisable, not only for the concerns of long-term safety
but also for the lack of short-term additive therapeutic
efficacy.40
Cyclosporine is sometimes used if other treatments are
not successful.42 The dosage of cyclosporine used ranged
from 3 mg/kg/d to 5 mg/kg/d. Both continuous long-term (up
to 12 months) and intermittent short-term courses (3 months
or 6 months) are efficacious. Continuous dosing is associated
with better efficacy and longer sustained effects relative to
intermittent use. However, adverse effects include infec-
tion, nephrotoxicity, and hypertension, and increased risk of
skin cancer and lymphoma should be monitored.
In those who do not respond to conventional treatment,
alternative diagnoses, lack of education and compliance,
hypersensitivity reactions to treatment, secondary skin in-
fections, other food and aeroallergens, or psychosocial
factors should be considered. Personalized medicine pos-
sesses a great potential to propel the development of new
therapeutic agents for severe AD.
5. Prevention
In 45% of children, the onset of AD occurs during the first 6
months of life, during the 1st year of life in 60%, and prior to
the age of 5 years in at least 85% of affected individuals.35
In those children with onset prior to the age of 2 years, 20%
will have persisting manifestations of the disease, and an
additional 17% will have intermittent symptoms by the age
of 7 years.43 Of those with AD during the first 2 years of life,
50% will have asthma during subsequent years.44 The main
risk factors for progression and persistence of asthma are
early onset, IgE sensitization, and severity of AD. Because
AD develops early in life and is the first step of the atopic
march, early prevention is very important. Primary pre-
vention is directed at preventing the clinical manifestations
of atopy by suppressing or delaying the onset of allergic
Atopic Dermatitis in Taiwan
sensitivity (Figure 2). Secondary prevention is directed at
reducing or removing triggers in the environment of the
sensitized individual. Comprehensive intervention pro-
grams dealing with both allergens and other potential
triggers appear beneficial.45
5.1. Skin management
Proper skin care consists of skin hygiene, moisturizing, and
avoidance of irritants and scratching.
5.1.1. Avoiding dry skin
Asian skin is more susceptible to being dry. Dry skin makes
children itch. Itchy skin leads to scratching, forming a vi-
cious cycle. The number one Asian skin care technique is to
moisturize. Baths are drying to the skin as is hot water.
Therefore, when taking a shower, lukewarm water and
bathing for 10e15 minutes is best.46 Skip the fancy shower
gels with fragrances and alcohol and use neutral or weakly
acidic pH soaps. After children step out of the bath or
shower, they should be put on any prescription medication,
and moisturizer should be applied within 3 minutes.46 If an
emollient is not applied within 3 minutes of leaving the
bath or shower, evaporation may cause excess drying of the
skin. Children with AD may use more skin care products
containing fragrance (phthalates), resulting in a higher in-
ternal burden of phthalates when they also have increased
transdermal absorption as indicated by the FLG P478S var-
iants.47 Thus, more attention should be paid to chemicals in
skin care products especially for FLG variant carriers.
5.1.2. Avoidance of irritants
Avoid irritants that cause a rash or make a rash worse.
These include detergents that dry the skin, perfumes,
scratchy clothing or bedding, and sweating. From Taiwan
Figure 2 Prevention of atopic march.
93
National Insurance data, the numbers of visits for AD were
highest in late spring to midsummer. This implies that
sweating is the common exacerbating factor in AD in hot
and humid climate.48
5.1.3. Controlling scratching
Upon scratching, staphylococcal superantigens may pene-
trate the skin barrier and contribute to the persistence and
exacerbation of allergic skin inflammation in AD.35 There-
fore, fingernails should be trimmed to help prevent damage
to the skin when scratching.
5.2. Dietary management
5.2.1. Avoiding allergens
These may include eggs, peanuts, milk, wheat, fish, or soy
products. Asians eat soy and drink soy milk. Determining
which allergens are contributing to AD is important.
Because the results of allergy tests are not always consis-
tent with symptoms, food cannot be restricted based only
on the result of a laboratory test. A food diary and chal-
lenge test are necessary for the confirmations. The Amer-
ican Academy of Paediatrics recommends that for babies
without symptoms, there is no need to restrict high aller-
genic foods and delay the introduction of complementary
foods beyond 4e6 months of age.49 If a certain food must
be avoided, appropriate diets that will not hamper normal
growth should be prepared by choosing a substitute food. A
few weeks of diet restriction and then slowly adding back
the food may also be tried without the eczema coming
back.50 According to a research by the German Paediatric
Academy, nonbreast-fed infants with confirmed cows-milk
protein allergy should receive an extensively hydrolysed
protein-based formula. Soy protein formula is an option
beyond 6 months of age. Cows-milk-based formula or other
unmodified animal milk proteins (e.g., goats milk, sheeps
milk) should be strictly avoided.51
5.2.2. Breastfeeding
A recent meta-analysis suggested that the incidence of in-
fantile AD is reduced by breastfeeding for at least 4
months.52 However, a recent study in Taiwan indicated that
increased duration of breastfeeding may increase the risk
of AD.53 However, we cannot exclude the other potential
benefits of breastfeeding. Sometimes, the maternal diet
can produce symptoms of AD.54 Mothers of exclusively
breastfed infants are suggested to restrict highly allergenic
foods if AD symptoms become severe in infants.
5.2.3. Supplements
5.2.3.1. Probiotics. Prenatal and postnatal probiotic sup-
plementation for prevention and treatment of pediatric AD
has been studied in clinical trials, but results have been
mixed and hindered by the heterogeneity of study design,
bacterial strains, dosages, and durations for different
allergic diseases of children.55,56 Current evidence is more
convincing for probiotics efficacy in prevention than
treatment of AD.56
5.2.3.2. Vitamin D. In addition to its classical role in cal-
cium homeostasis, vitamin D has been recognized for its
94
effect on immunomodulation. Studies have shown that
repletion of vitamin D results in decreased severity of AD in
individuals with AD who are deficient in vitamin D.57
Reduced vitamin D status in pregnancy may also be a risk
factor for the development of AD in the 1st year of life.58
5.2.3.3. Fish oil. Provision of fish oil, containing long-
chain n-3 polyunsaturated fatty acids, during pregnancy
may reduce sensitization to common food allergens and
reduce prevalence and severity of AD in the 1st year of life.
However, it is not clear if these are of clinical significance
and whether they persist.59
Other supplementation, such as prebiotics and black
currant seed oil (g-linolenic acid and u-3 combination), was
effective in reducing the development of AD and the
severity of AD.60
5.3. Environmental management
Children spend most of their time in indoor environments,
so reducing pollution in the indoor environment is impor-
tant for AD management. A study on the therapeutic effect
of a low-pollutant (PM10, formaldehyde, bacterial, and
mold suspension) ward also revealed that improvement of
the environment had a positive effect and reduced the
duration of treatment.61
5.3.1. Ventilation
Aeroallergens and pollutants from second-hand smoke, new
furniture, wallpaper, air conditioning, and cooking utensils
should be decreased by ventilation. An air cleaner is also
helpful.
5.3.2. Adequate humidity
Humidity should be maintained at about 50%. Excessive
humidity can promote the propagation of house dust mites,
fungi, and bacteria.
5.4. Psychological management
Stress-induced immunomodulation is altered in patients
with AD, but the exact mechanisms are not well under-
stood. Increased levels of nerve growth factor and sub-
stance P can be found in the plasma of patients with AD and
correlate positively with the disease activity.62 The nerve
growth factor levels were significantly higher in AD patients
than in controls.63 Maternal work stress was also reported
to be associated with AD.64 The most common problem in
severely affected AD children is exhaustion from not
sleeping well, leading to poor concentration at school. Poor
sleep efficiency in AD can be predicted by the Scoring
Atopic Dermatitis index, nocturnal melatonin secretion,
total serum IgE levels, and allergic sensitization to dust
mite and staphylococcal enterotoxins.65 Not only is treat-
ment of the AD indicated, but if behavioral, emotional, or
sleep abnormalities are noted, these should be tackled
early when intervention can be more effective. Improved
education and support for children with AD and their fam-
ilies may overcome the emotional burden and improve
quality of life.
I.-J. Wang et al
6. Conclusion
In conclusion, the complex interplay between the variety of
the environmental exposure and the interactions between
the genetic and epigenetic background are likely to affect
the development of AD. It is important to identify infants at
risk to provide early intervention. Prevention should start in
early life, a critical window of exposure. Repair of the
epidermal barrier in infants with AD may prevent the sub-
sequent atopic march. Beyond skin barrier repair, control of
inflammation and the itchescratch cycle is also important
for quality of life. Further studies for a tailored therapy for
AD in Asian children are warranted.
Conflicts of interest
The authors declare no conflicts of interest.
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